Dr. Castelino's long-term goal is to become an independently funded investigator with an expertise in mechanisms of fibrosis in scleroderma. The goal of her research is to study the roles of the lipid mediator lysophosphatidic acid (LPA) and its receptor LPA1 in scleroderma (SSc) dermal fibrosis. Dr. Castelino proposes to investigate the mechanisms by which the LPA-LPA1 pathway regulates dermal fibrosis, and determine the interplay of this novel pathway with TGF-, a central mediator in the pathogenesis of SSc. Her immediate objectives are to learn (1) new techniques in molecular biology including conditional gene targeting; (2) in vivo and in vitro experimentation with components of the TGF- pathway including v-integrins; and (3) skills for conducting translational research. As a junior faculty member at Massachusetts General Hospital (MGH), Dr. Castelino will benefit from interactions with basic scientists and clinical researchers. She will enhance her training through didactic seminars offered through MGH and the Harvard Clinical and Translational Science Center, and formal coursework at Harvard Medical School. Dr. Castelino will benefit from the mentorship of Drs. Andrew Tager and Robert Lafyatis and members of her advisory committee who have expertise in studying the pathogenesis of fibrosis, v-integrin biology and TGF- signaling, and translational research. In the first part of her proposal she will evaluate the roleof LPA-LPA1 signaling in myofibroblast accumulation in dermal fibrosis using transgenic mice to investigate fibroblasts specifically, and she will perform in vitro studies to evaluate fibroblast proliferation and apoptosis. In the second part of her proposal, she will investigate the role of LPA-LPA1 in TGF- activation, and assess whether v integrins are a key mediator of this process, by manipulating gene expression of the v-integrin subunit in vivo. In the final part of her proposal, she will evaluate the role of LPA-LPA1 signaling in SSc patients using peripheral blood and skin biopsy samples. Together these studies will characterize the mechanisms by which LPA and LPA1 mediate myofibroblast accumulation and TGF- signaling. These studies will serve as a foundation for Dr. Castelino to become an independent translational investigator. PUBLIC HEALTH RELEVANCE: Scleroderma is an autoimmune disease that affects multiple organs and causes fibrosis or hardening of the skin and internal organs. This disease is associated with high mortality, and to date there is no effective therapy. An improved understanding of the mediators that drive scleroderma fibrosis will hopefully result in better treatment options.